Abstract
An effective response to the ongoing coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will involve a range of complementary preventive modalities. The current studies were conducted to evaluate the in vitro SARS-CoV-2 antiviral and virucidal (irreversible) activity of astodrimer sodium, a dendrimer with broad spectrum antimicrobial activity, including against enveloped viruses in in vitro and in vivo models, that is marketed for antiviral and antibacterial applications. We report that astodrimer sodium inhibits replication of SARS-CoV-2 in Vero E6 and Calu-3 cells, with 50% effective concentrations (EC50) for i) reducing virus-induced cytopathic effect of 0.002-0.012 mg/mL in Vero E6 cells, and ii) infectious virus release by plaque assay of 0.019-0.032 mg/mL in Vero E6 cells and 0.030-0.037 mg/mL in Calu-3 cells. The selectivity index (SI) in these assays was as high as 2197. Astodrimer sodium was also virucidal, reducing SARS-CoV-2 infectivity by >99.9% (>3 log10) within 1 minute of exposure, and up to >99.999% (>5 log10) shown at astodrimer sodium concentrations of 10 to 30 mg/mL in Vero E6 and Calu-3 cell lines. Astodrimer sodium also inhibited infection in a primary human airway epithelial cell line. The data were similar for all investigations and were consistent with the potent antiviral and virucidal activity of astodrimer sodium being due to irreversible inhibition of virus-host cell interactions, as previously demonstrated for other viruses. Further studies will confirm if astodrimer sodium binds to SARS-CoV-2 spike protein and physically blocks initial attachment of the virus to the host cell. Given the in vitro effectiveness and significantly high SI, astodrimer sodium warrants further investigation for potential as a topically administered agent for SARS-CoV-2 therapeutic applications.
Highlights
The ongoing pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has resulted in unprecedented efforts to rapidly develop strategies to contain infection rates for the protection of vulnerable populations
In the repeat set of assays, astodrimer sodium was tested in the range of 0.0001 to 0.86 mg/mL to help further characterize the lower end of the dose response curve
Data from the current studies, taken together with studies of astodrimer sodium antiviral activity against human immunodeficiency virus-1 (HIV-1), and herpes simplex virus (HSV)-1 and -2, indicate that the compound exerts its antiviral activity against geographically diverse SARS-CoV-2 isolates by interfering with the early virus-cell recognition events
Summary
The ongoing pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has resulted in unprecedented efforts to rapidly develop strategies to contain infection rates for the protection of vulnerable populations. SARS-CoV-2 receptors and coreceptors have been shown to be highly expressed in nasal epithelial cells (Sungnak et al, 2020) This finding is consistent with the virus infectivity or replication pattern along the respiratory tract, which peaks proximally (nasal cavity) and is relatively minimal in the distal alveolar regions (Hou et al, 2020). These findings suggest that nasal carriage of the virus is a key feature of transmission, and that nasally administered therapeutic modalities could be potentially effective in helping to prevent spread of infection. Both size and surface charge contribute to the function of the compound (Tyssen et al, 2010), and when administered topically, astodrimer sodium is not absorbed systemically (Chen et al, 2009; O’Loughlin et al, 2010; McGowan et al, 2011)
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